1. Field of the Invention
This invention relates to monomer compositions useful in the formulation of biomedical adhesives and sealants, and methods of applying them to living tissue. More particularly, this invention relates to wound closure monomer compositions and their use for medical, surgical and other internal and external applications.
2. Background
Numerous methods and materials have been developed for biomedical sealants and adhesives including, for example, application to skin, hemostatic sealing of punctures and incisions in various living tissue, internal organs and blood vessels. For example, some of these methods utilize clotting agents, as set forth in U.S. Pat. Nos. 5,129,882 to Weldon et al., 5,221,259 to Weldon et al., and 5,330,446 to Weldon et al.; biocompatible adhesives cured or sealed by electromagnetic radiation, as set forth in U.S. Pat. No. 5,372,585 to Tiefenbrun; porous biodegradable patches or gauze, as set forth in U.S. Pat. Nos. 4,900,303 and 4,578,061 both to Lemelson; and plugs in the puncture sites of the vessel or organ, as set forth in U.S. Pat. Nos. 5,370,660 to Weinstein et al., 5,324,306 to Makower et al., 5,292,332 to Lee, 4,832,688 to Sagae et al., 5,053,046 to Janese, 5,108,421, 5,275,616, and 5,192,300 all to Fowler, and 4,852,568, 4,890,612, 5,061,274, 5,222,974, 5,282,827 and 5,021,059 all to Kensey et al. The subject matter of these patents is incorporated herein by reference.
Adhesives have been proposed as wound closure devices. One group of such adhesives is the monomeric forms of alpha-cyanoacrylates. Reference is made, for example, to U.S. Pat. Nos. 5,328,687 to Leung et al; 3,527,841 to Wicker et al.; 3,722,599 to Robertson et al.; 3,995,641 to Kronenthal et al.; and 3,940,362 to Overhults, which disclose alpha-cyanoacrylates that are useful as surgical adhesives. All of the foregoing references are hereby incorporated by reference herein.
Typically, the cyanoacrylate surgical adhesive is applied to one or both surfaces of wounds or incisions, including the internal portions of the wound, with any excess adhesive being quickly removed from the bonding surfaces. Subsequently, the edges of the wound are held together until they adhere. See U.S. Pat. No. 3,759,264 to Coover, Jr. et al.
A topical tissue adhesive commercially available is Histoacryl.RTM. available from B. Braun Melsungen AG of Germany. The manufacturer recommends use of this adhesive only for closure of minor skin wounds and not for internal use. Moreover the manufacturer recommends that the adhesive be used sparingly or in thin films because thick films do not increase the film strength and can lead to necrosis of surrounding tissue due to thermogenic reaction. Moreover, films formed from this adhesive are brittle, permitting severe dehiscence of wounds.
Thermogenic reactions of the above-mentioned tissue adhesives cause thermal damage (i.e., necrosis) of the tissue surrounding the adhesive upon which it is applied. Thermal damage to arterial tissue is described in an article entitled "Rate Process Model For Arterial Tissue Thermal Damage," Lasers In Surrerv And Medicine, vol. 15, pages 176-184, 1994. The primary effect heat has on arterial tissue is the denaturation of proteins. Collagen, one of the most abundant proteins in living tissue, has a relatively low denaturation threshold at 62-67.degree. C. The heating period for inducing thermal lesion in human aorta may range from 5 seconds at 73.degree. C. to 14.5 minutes at 66.degree. C.
Accordingly, there is a need for a surgical adhesive that does not cause thermal damage or necrosis of living tissue after application of the adhesive to the tissue.
Various methods and materials have been utilized in different applications that reduce heat of exothermic reactions, albeit not as biomedical adhesives or sealants. For example, U.S. Pat. No. 4,131,597 to Bluethgen et al. discloses a bioreactive composite material for prosthetic purposes. Heat of polymerization may be removed by rinsing, washing or irrigating with a biocompatible, nonaggressive, sterile cooling liquid.
U.S. Pat. No. 5,319,011 to Schoon discloses cyanoacrylate polymers and the effect of heat formed during the exothermic polymerization of the monomer. When used as a surface coating for nails, the exothermic reaction may cause blistering and burning of the nails and skin underlying the nails. Reduction of the heat generated may be accomplished using an organotin catalyst, which alters the exothermic nature of polymerization. U.S. Pat. No. 5,401,508 to Manesis discloses a hydrogel composition comprising water and a copolymer (abstract). The polymerization may be carried out in the presence of a small amount of a solvent to improve conversion and to flatten the exotherm peak. The polymerization is conducted in a mold and not in situ. Reaction exotherms are controlled to eliminate stress cracking and to obtain optimum conversion of monomers. U.S. Pat. Nos. 4,900,546 and 5,258,420, both issued to Posey-Dowty et al., disclose a bone cement for sustained release of therapeutic substances. The cement composition comprises a liquid monomer and therapeutic substances. An emulsifier may also be added to the cement composition, which also serves to dissipate the heat formed during exothermic polymerization of the monomer. The emulsifier is mixed in the monomer in an amount of about 0.1 to about 10.0 wt. % The cement is applied to bone and subsequently polymerized. U.S. Pat. No. 4,042,442 to Dombroski et al. discloses alphacyanoacrylate adhesive compositions and initiators for promoting the polymerization of adhesive compositions. The polymerization of the adhesive compositions may be accelerated by either treating the surface to be bonded with a basic material or by adding a small amount of a basic catalyst to the adhesive just prior to use.
U.S. Pat. No. 3,995,641 to Kronenthal et al. discloses carbalkoxyalkyl 2-cyanoacrylates as surgical adhesives (abstract). The heat of polymerization and the time required to reach maximum exotherm is also disclosed. Use of a carbalkoxyalkyl component modifies the chemical reaction mechanism. U.S. Pat. No. 4,793,330 to Honeycutt et al. discloses an orthopedic cast system wherein a fabric treated with wax is used to absorb the heat of exothermic reaction. The waxes may be used in combination with solvents or emulsifiers. An .alpha.-cyanoacrylate is utilized as a hardening agent and not as an adhesive. Additionally, the cyanoacrylate does not come into direct contact with the skin because a barrier fabric is placed on the skin prior to application of the cyanoacrylate. U.S. Pat. No. 4,187,559 to Grell et al. discloses a body joint endoprosthesis. The patent also discloses the effect of the heat of polymerization of a monomer on a tissue. The monomer is used to cement implants to the bone. To eliminate the negative effects of excessive heat, the cement is eliminated from the implant procedure altogether.
Other methods utilize various materials to catalyze surfaces to initiate polymerization of monomeric compositions. U.S. Pat. No. 3,759,264 to Coover, Jr. et al. discloses a surgical .alpha.-cyanoacrylic acid adhesive for joining tissue surfaces together. Catalysts or accelerators may be used to rapidly form a bond. The catalysts are normally applied to the surfaces of the tissues to be bonded with subsequent application of the adhesive. Suitable polymerization catalysts or accelerators include solutions of aliphatic alcohol, such as methanol, isobutanol, capryl, etc. U.S. Pat. No. 2,768,109 to Coover, Jr. discloses a method of bonding a material exhibiting an acidic surface character, which comprises moistening the surface to be bonded with an alkyl monohydric alcohol bonding promoter and thereafter applying to the surface a film of an adhesive composition comprising alpha cyanoacrylate monomer. A high volatile bonding promoter is used to enable evaporation of the promoter and thereby eliminate excess promoter. The cyanoacrylates are used in bonding a variety of materials.